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1.
AAPS PharmSciTech ; 21(3): 99, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32133549

RESUMO

The objective of the present investigation was to understand the effect of sucrose acetate isobutyrate (SAIB) on abuse-deterrent properties (ADPs) of abuse-deterrent formulations (ADFs) based on Polyox™. SAIB would enhance ADPs of Polyox™-based formulations due to its glassy liquid and hydrophobic properties. Formulations were prepared by granulation followed by compression and heat curing at 90°C. The formulations were evaluated for surface morphology, hardness, manipulation in coffee grinder, particle size distribution, drug (pseudoephedrine hydrochloride) extraction in water, alcohol, 0.1 N HCl, 0.1 N NaOH at room temperature and elevated temperature using microwave and oven, syringeability and injectability, and dissolution. The heat curing of formulations significantly increased the hardness (> 490 N). Addition of SAIB imparted elasticity to formulations and decreased brittleness as indicated by lower values of work done and gradient compared to control formulations. After grinding, about 7.7-25.6% of the powder remained on the sieve (1 mm pore opening), D90 was 53.1-136.7 µm more, and Q (fraction < 500 µm) was 17.8-40.7% less in SAIB-based formulations compared to control formulations. Drug extraction between control and test intact formulations was similar. However, drug extraction was 23.9-42.5% (water), 20.6-26.1% (0.1 N HCl), and 37.4-50.6% (0.1 N NaOH) less in SAIB-based powder cured and uncured formulations compared to control formulations. Dissolution varied from 65.6 ± 4.2 to 97.6 ± 4.0% in 9 h from the formulations. In conclusion, addition of SAIB to Polyox™-based ADFs has synergistic effect on ADPs. This would further decrease potential of drug abuse/misuse by various routes.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Sacarose/análogos & derivados , Formulações de Dissuasão de Abuso/tendências , Composição de Medicamentos/tendências , Desenvolvimento de Medicamentos/tendências , Dureza , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/metabolismo , Tamanho da Partícula , Pós , Sacarose/administração & dosagem , Sacarose/química , Difração de Raios X/métodos , Difração de Raios X/tendências
3.
Int J Pharm ; 577: 119042, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953084

RESUMO

Prescription opioids have widely been abused as an epidemic. In this research, we developed a drug composition based on the crosslinked carboxymethylcellulose (XCMC) and a drug model that can effectively deter abuse by injection via multiple mechanisms. The anionic nature of the XCMC is responsible for complexing the cationic opioids in aqueous solutions, minimizing the free drug amount accessible for extraction. The crosslinked nature of the polymer is responsible for its swelling and partial containment of the drug solution within the swollen polymer's network, thus minimizing the available volume for subsequent injection. We have shown that XCMC can efficiently interact with cationic drugs in the form of physical blends and chemical complexes in different aqueous solvents, forming abuse-deterrent complexes. The complexation efficiency was affected by the solution pH and ionic strength, as well as the drug to polymer ratio in the formulation. The in vitro dissolution studies were conducted in two stages, the stage I in 0.1 M HCl and the stage II in water and pH 7.5 phosphate buffer. These studies confirmed the proper drug release under the legitimate conditions of use. Therefore, the XCMC polymers have a great potential to be used as deterring agents in developing opioid medications with abuse-deterrent properties.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/administração & dosagem , Carboximetilcelulose Sódica/química , Analgésicos Opioides/química , Química Farmacêutica , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Concentração Osmolar , Solventes/química , Abuso de Substâncias por Via Intravenosa/prevenção & controle
4.
Pain Pract ; 19(4): 443-454, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30597739

RESUMO

Providers who treat patients with chronic pain face a dual challenge: providing adequate access to opioid therapies for appropriate pain management while adopting strategies to minimize the risk for abuse. Commonly prescribed opioids have substantial abuse potential when administered intravenously, and extended-release (ER)/long-acting (LA) opioids may be targeted for IV abuse because of the higher per-dose medication level. The consequences of IV opioid abuse are severe and increase the risks for adverse outcomes, including mortality due to acute health events, serious infections, and deep vein thrombosis, to name a few. To reduce the potential for abuse of prescription opioids by both recreational and experienced drug abusers, abuse-deterrent formulations (ADFs) of opioid medications employ either physical/chemical barriers or agonist-antagonist combinations. Here we review the development and use of opioid ADFs as a harm-reduction strategy, and their potential for mitigating IV opioid abuse. The approved ER/LA opioids with ADF labeling in the United States include formulations of oxycodone, hydrocodone, and morphine. Findings from in vitro laboratory tests of abuse deterrence for opioid ADFs are described herein, as are data from human abuse potential studies for IV abuse of those ADF products, for which such studies are feasible (ie, abuse-deterrent agonist-antagonist formulations). The available ADF opioids may decrease both the attractiveness and the feasibility of IV abuse. The adoption of ADF opioids represents one tactic for providing access to needed medication for patients with chronic pain, while potentially reducing the risk for opioid abuse, in a comprehensive effort to combat the opioid epidemic.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Manejo da Dor/métodos , Dor Crônica/tratamento farmacológico , Preparações de Ação Retardada/administração & dosagem , Composição de Medicamentos , Humanos , Manejo da Dor/efeitos adversos , Estados Unidos
6.
Clin Pharmacol Ther ; 103(6): 924-935, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29878319

RESUMO

The analgesic, sedative, antidepressant, euphoriant, intoxicating, and addictive properties of opium and its synthetic derivatives are well known and have been known for centuries. Hence, the current major public health problems due to excessive availability should be no surprise. What is unprecedented in the United States, and emerging elsewhere, is the extent of the profound consequences and complexity of addressing this public health crisis.


Assuntos
Analgésicos Opioides/provisão & distribução , Overdose de Drogas/epidemiologia , Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Comorbidade , Descoberta de Drogas/organização & administração , Controle de Medicamentos e Entorpecentes/organização & administração , Fidelidade a Diretrizes , Pessoal de Saúde/educação , Humanos , Síndrome de Abstinência Neonatal/epidemiologia , Síndrome de Abstinência Neonatal/terapia , Transtornos Relacionados ao Uso de Opioides , Testes Farmacogenômicos/métodos , Guias de Prática Clínica como Assunto , Saúde Pública , Estados Unidos/epidemiologia
7.
Pain Res Manag ; 2018: 7276021, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849845

RESUMO

Objective: To investigate the pharmacokinetics (PK) of Morphine ARER, an extended-release (ER), abuse-deterrent formulation of morphine sulfate after oral and intranasal administration. Methods: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study assessed the PK of morphine and its active metabolite, M6G, from crushed intranasal Morphine ARER and intact oral Morphine ARER compared with crushed intranasal ER morphine following administration to nondependent, recreational opioid users. The correlation between morphine PK and the pharmacodynamic parameter of drug liking, a measure of abuse potential, was also evaluated. Results: Mean maximum observed plasma concentration (Cmax) for morphine was lower with crushed intranasal Morphine ARER (26.2 ng/mL) and intact oral Morphine ARER (18.6 ng/mL), compared with crushed intranasal ER morphine (49.5 ng/mL). The time to Cmax (Tmax) was the same for intact oral and crushed intranasal Morphine ARER (1.6 hours) and longer for crushed intranasal morphine ER (1.1 hours). Higher mean maximum morphine Cmax, Tmax, and abuse quotient (Cmax/Tmax) were positively correlated with maximum effect for drug liking (R2 ≥ 0.9795). Conclusion: These data suggest that Morphine ARER maintains its ER profile despite physical manipulation and intranasal administration, which may be predictive of a lower intranasal abuse potential compared with ER morphine.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/farmacocinética , Morfina/farmacocinética , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Administração Intranasal , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Área Sob a Curva , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Morfina/administração & dosagem , Morfina/sangue , Fatores de Tempo , Adulto Jovem
8.
Clin Drug Investig ; 38(7): 573-577, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29651781

RESUMO

The US Food and Drug Administration (FDA) is encouraging the innovation of long-acting opioid formulations that are manipulation-resistant. The purpose of this commentary is to assess the benefits and limitations of abuse-deterrent opioid formulations (ADFs) and discuss their role in mitigating the current opioid epidemic. ADFs have been created with chemical properties that make it difficult for people who non-medically use prescription drugs to crush and dissolve opioid tablets, as well as by combining opioids with antagonists such as naloxone or naltrexone, which are released only when the dosage form has been manipulated or the drug is taken by a non-intended route. Despite these and other technologies, consensus regarding the effectiveness of these formulations in preventing non-medical use is lacking given the difficulty in obtaining post-marketing data. Researchers also question if the creation of abuse-deterrent drugs will have a positive effect on those struggling with a severe opioid-use disorder, fearing that current opioid users will simply find a new - perhaps more dangerous - drug of choice. Abuse-deterrent opioids are still opioids, and although they may make manipulation more difficult than non-ADF formulations, they are not "abuse proof." The introduction of ADFs could provide a false sense of security among prescribers and dispensers, and we fear that ADFs may have a minimal impact on non-medical use of prescription opioids. Further epidemiological studies will be required to determine the large-scale impact of abuse-deterrent opioids in preventing opioid use disorder and its downstream consequences.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , United States Food and Drug Administration , Formulações de Dissuasão de Abuso/tendências , Analgésicos Opioides/administração & dosagem , Química Farmacêutica/métodos , Composição de Medicamentos , Humanos , Naltrexona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Estados Unidos/epidemiologia , United States Food and Drug Administration/tendências
9.
Curr Opin Support Palliat Care ; 12(2): 124-130, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29465470

RESUMO

PURPOSE OF REVIEW: The primary cause of overdose death in the United States is related to pharmaceutical opioids. A few particular populations that struggle with adverse outcomes related to opioid abuse are those in palliative care, those with chronic pain, and those receiving pain treatments secondary to cancer or chemotherapy. RECENT FINDINGS: There have been massive efforts to decrease the use of opioid abuse in patient care in a gestalt manner, but palliative care provides unique challenges in applying these reduction tactics used by other specialties. SUMMARY: We explore behavioral interventions, provider education, alternative pain management techniques, postmarketing surveillance, and abuse-deterrent formulas as emerging methods to counteract opioid abuse in these populations.


Assuntos
Analgésicos Opioides/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor Crônica/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Desvio de Medicamentos sob Prescrição/estatística & dados numéricos , Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Preparações de Ação Retardada , Humanos , Transtornos Relacionados ao Uso de Opioides/mortalidade , Manejo da Dor/métodos , Cuidados Paliativos , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Desvio de Medicamentos sob Prescrição/prevenção & controle , Vigilância de Produtos Comercializados/métodos , Estados Unidos
10.
Clin Ther ; 40(2): 334-344, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29398162

RESUMO

PURPOSE: This commentary examines the development, regulatory, and reimbursement challenges facing abuse-deterrent formulation (ADF) products. METHODS: In January 2017, the Tufts Center for the Study of Drug Development convened a roundtable to explore clinical development, regulatory, and reimbursement challenges with respect to ADFs of opioid analgesics. Roundtable participants, who included a range of pharmaceutical industry and other experts, discussed multiple challenges. FINDINGS: First, several key clinical development challenges were identified and discussed. These challenges pertain to prodrug development and development of deterrents against oral abuse. Second, experts suggested that more clarity is needed from regulatory authorities regarding standards for proving ADF labeling claims and for being rewarded with 3-year data exclusivity. Similarly, given the substantial burdens associated with the development of postapproval evidence generation, experts raised the need for a consistent regulatory policy related to postapproval evidence generation for all ADFs (branded and generic). Third, despite the public health benefits of certain ADF products, current coverage and access policies impede patient access. Payer justification for restrictive policies appears to be based more on budget impact considerations than cost-effectiveness. Fourth, there remains a need to further expand the evidence base regarding clinical and cost-effectiveness as well as abuse deterrence in a real-world setting for all ADF products. IMPLICATIONS: Clinical development challenges need to be overcome with respect to novel ADF technologies, such as prodrugs and deterrents against oral abuse. More clarity is needed from regulatory authorities on labeling claims and data exclusivity eligibility with respect to ADFs. Ensuring prescriber training and awareness of various options for treating pain, including ADF products, is an important step, as is educating payers about the public health benefits of ADFs in appropriate subpopulations of pain patients. In addition, physicians may need to incorporate appropriate risk stratification methods. Finally, it is important to establish a level playing field between coverage of ADF and non-ADF products so that non-ADF products are not given preferred formulary placement.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Química Farmacêutica/métodos , Humanos , Dor/tratamento farmacológico
12.
Pain Med ; 18(7): 1303-1313, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27651506

RESUMO

Objective: Misuse and abuse of prescription opioids remains a major healthcare concern despite considerable efforts to increase public awareness. Abuse-deterrent formulations of prescription opioids are designed to reduce intentional misuse, abuse, and prescription opioid-related death. A novel extended-release (ER) formulation of morphine (Morphine ARER; MorphaBond™) resists physical manipulation and retains the drug's ER characteristics, even if attempts are made to manipulate the formulation. Design: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study investigated the abuse potential and safety of crushed intranasal and intact oral Morphine ARER compared with commercially available crushed intranasal ER morphine sulfate (ER morphine). Outcome Measures: Endpoints included maximum mean drug liking (E max ) as measured by subjects on a bipolar 100 mm visual analog scale (primary), a subject's desire to take the drug again, good effects of the drug, and drug high. Results: Twenty-five subjects completed the treatment phase. There was a 40% reduction in E max for crushed intranasal Morphine ARER compared with crushed intranasal ER morphine ( P < .0001). There was no significant difference when comparing the E max for crushed intranasal vs intact Morphine ARER. When comparing crushed intranasal Morphine ARER with ER morphine, subjects reported lower mean scores for good effects of the drug, drug high, and overall drug liking, as well as a lower desire to use Morphine ARER again. Other than adverse events associated with intranasal administration of a drug, all adverse events were typical of those reported for opioid-containing drugs. Conclusions: Overall, these data suggest that Morphine ARER has a lower abuse potential via the intranasal route of administration when compared with ER morphine.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Administração Intranasal , Adulto , Analgésicos Opioides/química , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Método Duplo-Cego , Composição de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Morfina/química , Transtornos Relacionados ao Uso de Opioides/psicologia , Adulto Jovem
13.
Pain Med ; 18(9): 1695-1705, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27651510

RESUMO

Objective: To compare the relative human abuse potential after insufflation of manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine ER tablets. Methods: A randomized, double-blind, double-dummy, active- and placebo-controlled five-way crossover study was performed with adult volunteers who were experienced, nondependent, recreational opioid users. After intranasal (IN) administration of manipulated high-volume (HV) morphine-ADER-IMT (60 mg), participants were randomized (1:1:1:1) to receive IN manipulated low-volume (LV) morphine ER (60 mg), IN manipulated LV morphine-ADER-IMT, intact oral morphine-ADER-IMT (60 mg), and placebo in crossover fashion. Pharmacodynamic and pharmacokinetic assessments included peak effect of drug liking (E max ; primary endpoint) using drug liking visual analog scale (VAS) score, E max using overall drug liking, and take drug again (TDA) VASs scores, and mean abuse quotient (AQ), a pharmacokinetic parameter associated with drug liking. Results: Forty-six participants completed the study. After insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT, drug liking E max was significantly lower ( P < 0.0001) compared with IN morphine ER. Overall drug liking and TDA E max values were significantly lower ( P < 0.0001) after insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT compared with IN morphine ER. Mean AQ was lower after insufflation of HV (9.2) and LV (2.3) morphine-ADER-IMT or ingestion of oral morphine-ADER-IMT (5.5) compared with insufflation of LV morphine ER (37.2). Conclusions: All drug liking, take drug again, and abuse quotient endpoints support a significantly lower abuse potential with insufflation of manipulated morphine-ADER-IMT compared with manipulated and insufflated non-AD ER morphine.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Administração Intranasal , Administração Oral , Adulto , Analgésicos Opioides/farmacocinética , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Masculino , Morfina/farmacocinética , Comprimidos
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